No abstract

Inorganic polyphosphates (polyP) are polymers composed of phosphate residues linked by energy‐rich phosphoanhydride bonds. As polyP can bind calcium, the hypothesis of this study is that polyP enters chondrocytes and exerts its anabolic effect by calcium influx through calcium channels. PolyP treatment of cartilage tissue formed in 3D culture by bovine chondrocytes showed an increase in proteoglycan accumulation but only when calcium was also present at a concentration of 1.5 mM. This anabolic effect could be prevented by treatment with either ethylene glycol‐bis(β‐aminoethyl ether)‐N,N,N',N'‐tetraacetic acid or the calcium channel inhibitors gadolinium and nifedipine. Calcium and polyP cotreatment of chondrocytes in monolayer culture resulted in calcium oscillations that were polyP chain length specific and were inhibited by gadolinium and nifedipine. The calcium influx resulted in increased gene expression of sox9, collagen type II, and aggrecan which was prevented by treatment with either calphostin, an inhibitor of protein kinase C, and W7, an inhibitor of calmodulin; suggesting activation of the protein kinase C‐calmodulin pathway. Tracing studies using  4′,6‐diamidino‐2‐phenylindole, Mitotracker Red, and/or Fura‐AM staining showed that polyP was detected in the nucleus, mitochondria, and intracellular vacuoles suggesting that polyP may also enter the cell. PolyP colocalizes with calcium in mitochondria. This study demonstrates that polyP requires the influx of calcium to regulate chondrocyte matrix production, likely via activating calcium signaling. These findings identify the mechanism regulating the anabolic effect of polyP in chondrocytes which will help in its clinical translation into a therapeutic agent for cartilage repair.

Objectives Emergency department (ED) return visits (RVs) leading to hospital admission are a quality measure that can potentially signal gaps in patient care. Systematic capture and investigation of RVs at a case level can provide an understanding of patient- and visit-level factors associated with RVs, and thus inform system-level quality improvement (QI) opportunities. Our objective is to describe the development of a database that enables tracking and analyzing of all pediatric ED RVs, to understand recurring themes and inform QI initiatives. Methods A single-center retrospective cohort study was conducted at a quaternary care children's hospital during a 3-year period (December 2013 to November 2016). All 72-hour RVs were audited for patient- and visit-level variables and clinicians completed root-cause analyses of their RVs. Using descriptive statistics, variables associated with RVs and system-level quality themes were identified. Results Of 214,047 ED patient visits, 1546 (0.7%) patients returned within 72 hours and were admitted. The RV patients had higher acuity scores on both visits compared with all ED visits, and the RV group had a higher proportion of children younger than 12 months than the overall ED visit group (25.0% vs 16.2%). The underlying cause for the majority of RVs was determined to be natural disease progression (63%), whereas 9% were callbacks for positive blood cultures or discrepant radiology results, and 6% were categorized as misdiagnoses. Several successful QI initiatives were completed as a result of the program. Conclusions Systematic monitoring and investigation of all ED RVs provides an innovative and effective approach to seeking provider- and system-level improvement opportunities.